Coronary artery disease is the principal cause of myocardial infarction (MI) and a leading cause of hospitalization and mortality in the veteran population. A consequence of MI is congestive heart failure (CHF), which is secondary to defective myocardial remodeling post-infarct. Recent studies have demonstrated a significant role for inflammation and immune cells in cardiac remodeling, particularly infiltrating monocyte/macrophage cells in cardiac repair. We recently determined that the oral immunosuppressant FTY720 is cardioprotective and increases survival in mouse models of coronary ligation and accelerated atherosclerosis leading to heart failure. While FTY720 has been shown to exert direct protective cell signaling effects in cardiac myocytes, its effects on immune cells, which result in cardioprotection have not been delineated. Our proposal focuses on our central hypothesis that cardiac ischemic injury initiates an inflammatory response that promotes abnormal cardiac remodeling which can be interrupted by immune modulation. Our proposal will determine specific changes in immune cells following FTY720 treatment that correlate with improved outcomes and determine if an optimal window for protective immune modulation exists following an ischemic event. By identifying specific changes induced by immune modulation, we will determine mechanisms that initiate beneficial cardioprotective immune responses that will be useful to target therapeutically and identify biomarkers that reflect the pathological aspects of the immune responses to MI. We will investigate the hypothesis that FTY720 improves cardiac repair following an ischemic event by altering the influx, phenotype and function of cardiac monocyte-derived macrophages. We will explore potential cardioprotective mechanisms for FTY720 effects: 1) a direct effect of FTY720 on macrophage polarization and/or 2) a primary effect of FTY720 on lymphocyte egress. We will also determine whether a short, critical period of FTY720-driven immune modulation can improve outcomes in an ischemia-reperfusion model. Aim 1: Determine if FTY720 treatment alters post-infarct cardiac macrophage phenotype and function. Aim 2: Determine if cardio-protective effects of FTY720 against ischemic injury are dependent on B lymphocyte trafficking. Aim 3: Determine if a limited window of FTY720 treatment is cardioprotective following ischemic injury. Our multi-PI proposal leverages the expertise of established investigators with diverse areas of expertise in cardiac remodeling, immunity and macrophage biology. Together we are well positioned to explore how modulation of immunity can impact and improve cardiac repair. Significantly, our findings will define mechanisms by which FTY720 improves post-ischemic cardiac remodeling and survival, which could lead to new therapeutics to improve repair post-MI and decrease CHF. Our project is novel in that it seeks to define a mechanism of beneficial immune modulation in the post-ischemia setting and will identify how FTY720 alters cardiac inflammation post-ischemia/reperfusion injury and the cell types responsible for cardioprotection.